beta-substituted aminoalkyl 2,6-dialkylsubstituted benzoates and method of making the same



fl-SUBSTITUTED AMENOALKYL 2,6-DIALKYLSUB- STITUTED BENZGATES AND METHOD OF MAK- ING- THE SAME Norman Rahiohn, (Ioluinbia, Mm, assignor to Curators of the University of Missouri, Columbia, Mo., a public corporation of Missouri No Drawing. Application May 27, 1954 Serial No. 432,918

12 Claims. (Cl. 260-477) The present invention relates to novel chemical compounds; and, more particularly, the invention relates to [i-substituted aminoalkyl dialkylsubstituted benzoates and salts thereof possessing valuable pharmacological properties.

e-Diethylaminoethyl p-aminobenzoate (procaine) and its salts, such as the hydrochloride, and fl-dimethylaminoethyl p-butylaminobenzoate hydrochloride (tetracaine hydrochloride) are well known local anesthetics. The physiological effect of such compounds is limited in duration, decreasing relatively rapidly as time .elapses after injection. 7

t is the principal object of the present invention to provide novel chemical compounds possessing valuable pharmacological properties;

It is another object of the invention to provide novel chemical compounds possessing local anesthetic properties.

A further object of the invention is to provide novel chemical compounds possessing local anesthetic properties comparable to those of procaine and tetracaine which, however, upon injection, provide a local anesthetizing eiiect of substantially longer duration than do the, prior compounds.

Other objects will become apparent from a consideration of the following specification and claims.

The novel compounds of the present invention are ,3- substituted aminoalkyl 2,6-dialkylsubstituted benzoates possessing the fundamental structure:

(Hig -CH2 CH CHz It will be noted from the foregoing thatthe compounds within the general formula are related to procaine and tetracaine. Nevertheless, although the compounds of the invention'possess local anesthetic properties on the order of procaine and tetracaine, they possess a further property not possessed by either of these local anesthetics, namely extended duration of anesthetizing effect upon injection. The exact reason for this is not fully understood. However, in the light of tests with procaine, on the one hand, and the compounds of the invention, on the other hand, it would appear that the relatively rapid loss of elfect after injection of the procaine or tetracaine is due to hydrolysis of the ester group in the presence of enzymes. The compounds of the present invention possess, however, marked resistance to hydrolysis, and this is believed to be due to a steric hindering effect provided by the alkyl substituents ortho to the ester group. At any rate it has been found that compounds of the invention have, in addition to a much lower rate of hydrolysis, a substantially longer anesthetizing eifect as compared to compounds related but for the ortho substituents. For example, equianesthetic solutions of the compounds produce, in comparison with the common clinically-employed procaine and tetracaine, several times longer duration of topical and intracutaneous anesthesia in man and animals. This duration is even greater When the compounds are employed in ointment form.

As stated, in the compounds of the invention each of the positions on the benzene ring ortho to the ester group is provided with an alkyl substituent. These alkyl groups, R and R in the above formula, may contain from 1 to 3 carbon atoms, such as methyl, ethyl or propyl. In any one compound R and R may be the same or may be different, although from the standpoint of ease of manufacture it is preferred that R and R be the same groups.

The remaining substituents on the benzene ring, namely R R and R may be hydrogen or one or more thereof may be a simple alkyl group of the type mentioned above with respect to R and R The ester group of the compounds is a fl-disubstituted aminoalkyl group,

Rs R is a saturated aliphatic chain containing from 2 to 4 carbon atoms, and since the ester group, as stated, is a fi-substituted aminoalkyl group, R will be an ethylene or alkyl-substituted ethylene chain. Thus, R may be ethylene itself, 1 methylethylene, 2 methylethylene, 1,2 dimethylethylene, 1,1 dimethylethylene or 2,2 dimethylethylene. R7 and R may be alkyl groups containing from 1 to 4 carbon atoms such as methyl, ethyl, propyl or butyl groups. It is advisable, however, that the total number of carbon atoms in R plus R not exceed six. Hence, Where R for example, is a butyl group, R will be a methyl or ethyl group, and so on. R and R may also join to proviae a pentamethylene chain attached to the nitrogen atom to provide the group CH2C H2 CH9 (Hie-C 2 The preferred compounds from the standpoint of optimum local anesthetic action and duration of effect are those possessing the fundamental structure:

CH2OH3 3. the group consisting of hydrogen and alkyl groups containing from 1 to 3 carbon atoms.

In the compounds of the invention there is a basic nitrogen'in the ester groupto whichan equivalent of acid may be added to form a salt. Hence, the compounds of the invention may be prepared and/ or employed either as the base or as a salt. Thus, for example, the structural formula for the hydrochloride of the compounds of the present invention may be written as follows:

I All-O ReN Rs R1 B] Rs- -R In view of the fact that the salts differ from the bases only in the addition of acid to the nitrogen atom referred to, and are characterized by the same fundamental structural formula, the salts as well as the bases are included within the scope of this application and of the claims wherever reference is made to compounds having a stated fundamental structure.

The acid forming the salt may be any inorganic or organic acid desired, for example, hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, and the like; acetic, propionic, caproic, stearic, and other acids of this series, and the like; crotonic, oleic, oxalic, citric, tartaric, lactic, benzoic, naphthoic, picric, salicylic, dilituric, methane sulfonic, camphor sulfonic, and the like. When a salt is to be administered, any toxicity or other undesirable effect which may be imparted by the acid will be taken into consideration as well known in the art.

The compounds may be readily prepared by reacting one mole of the appropriate 2,6-dialkyl substituted benzoic acid,

where the various R groups are as discussed above, with one mole of the appropriate fl-disubstituted aminoalkyl chloride hydrochloride in the presence of two equivalents of a weakly alkaline material insoluble in the reaction mixture, such as potassium bicarbonate or sodium bicarbonate, which neutralizes the hydrogen chloride of the reactant and produced during the reaction. The reaction is preferably carried out under anhydrous conditions using, for example, dry toluene as solvent. Elevated temperatures speed the reaction, and refluxing is recommended. The product can be separated from the reaction medium by any one of a wide variety of means. The material thus obtained can be worked up following conventional techniques for purification.

The base may be readily converted to the desired salt by treatment with the appropriate acid. For example, in converting the base to the hydrochloride, it may be treated, while in solution, for example, in toluene, with anhydrous gaseous hydrogen chloride.

The 2,6-dialkyl substituted benzoic acids referred to above may be readily prepared by any one'of a variety of procedures known in the art and recorded in the 4. literature. For instance the appropriate 2,6-dialkyl substituted benzene,

Rl- R2 where the various R groups are as described above, may he brominated to attach a bromine atom to the ring carbon atom between R; and R The resulting brornobenzene may then be converted to the corresponding carboxylic acid in accordance with the Grignard reaction.

The compounds of the invention and their preparation will be more readily understood by a consideration of the following specific examples which are given for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

EXAMPLE I 2,6-dimethylbenzenediazonium chloride, prepared in the usual manner from 50 g. 2,6-dimethylaniline, is added to a cold suspension of mercuric bromide formed by treating 71 g. of mercuric nitrate with 103 g. of sodium bromide in 300 ml. of water. The complex is collected by filtration and dried. It is then mixed with 350 g. of finely ground sodium bromide, and the mixture added slowly to a flask heated to C. in an oil bath. After decomposition is complete, the reaction mixture is extracted repeatedly with benzene. The combined benzene extracts are washed with dilute hydrochloric acid, dilute sodium hydroxide solution and water. The benzene is removed by distillation on a steam bath, and the residue is distilled under vacuum to give 2,G-dimethylbromobenzene, boiling at l0l103 C./22 mm.

A Grignard reagent is prepared in the usual manner from 18.5, g. of the 2,6-dimethylbromobenzene, 2.6 g. of magnesium, a small amount of ethyl bromide and ml. anhydrous ether. The Grignard solution is poured onto Dry Ice, and, after the latter has evaporated, the reaction mixture is acidified with dilute hydrochloric acid.. The ether layer is separated and worked up to yield 2,6-dimethylbenzoic acid melting at 1l3115 C.

A mixture of 6 g. (0.04 mole) of 2,6-dimethylbenzoic acid, 8.3 g. (0.083 mole) of potassium bicarbonate, 8.3 g. (0.048 mole) of fl-diethylaminoethyl chloride hydrochloride and ml. of toluene is refluxed under a Stark and Dean trap, to remove water, for 30 hours. The reaction mixture, after being allowed to cool, is washed with dilute sodium hydroxide solution and water and then dried over anhydrous magnesium sulfate. The dry toluene solution is treated with anhydrous hydrogen chloride to precipitate S-diethylaminoethyl 2,6-dimethylbenzoate hydrochloride which melts at 16l164 C. after recrystallization from a mixture of absolute ether and absolute alcohol.

The calculated C and H analysis for C H O NCI is: C, 63.0; H, 8.4; that found is: C, 62.9; H, 8.3.

A 1% solution of this compound administered intracutaneously anesthetizes the skin of a guinea pig for 45-60 minutes.

. EXAMPLE II Mesitylene is brominated according to the procedure of L. I. Smith, Organic Synthesis, Coll. Vol. II, p. 95, to give bromomesitylene boiling at 110-112 C./l8 mm.

This bromomesitylene is then converted to mesitoic acid (2,4,6-trimethylbenzoic acid) by the method of R. P. Barnes, Organic Synthesis, 21, p. 77 (1941), using 95 g. of bromomesitylene, 12.1 g. of magnesium, 380 mLof dry ether and an excess of Dry Ice.

A- mixture of 8.2 g. (0.05 mole) of 2,4,6-trimethylbenzoic acid, 10.4 g. (0.06 mole) of B-diethylaminoethyl chloride hydrochloride, 11.0 g. (0.11 mole) of potassium bicarbonate and 200 ml. of toluene is refluxed under a Stark and Dean trap for 22 hours. The reaction mix ture, after being permitted to cool, is washed twice with sodium hydroxide solutions and once with water, and then dried over anhydrous magnesium sulfate. The dry toluene solution is treated with anhydrous hydrogen chloride and the precipitate collected. Recrystallization of the precipitate from a mixture of absolute alcohol and absolute ether, results in p-diethylaminoethyl 2,4,6- trimethylbenzoate hydrochloride melting at 182-1835 C.

The calculated C and H analysis for C I -I Q NCl is: C, 64.1; H, 8.7; that found is: C, 64.1; H, 9.0.

A 1% solution of this compound injected intracutaneously anesthetizes the skin of a guinea pig for 55-70 minutes.

Following the foregoing procedure but using 13-,dimethylaminoethyl chloride hydrochloride or B-diisopropylamirwethyl chlori hydro h orid i ac f t fiylaminoethyl chloride hydrochloride the corresponding padimethylaminoethyl 2,4,6-trimethylbenzoate hydrochloride and fl-diisopropylaminoethyl 2,4,6-trimethylbenzoate hydrochloride may be prepared.

EXAMPLE III Following the procedure of Newman and Lloyd, J. Am. Chem. Soc. 74, p. 2672 (1952), bromodurene (boiling at 120-123 C./ 15 mm.) is prepared from 26 g. of durene and 33.4 g. of bromine.

Following the procedure also set forth in the abovecited article, 24 g. of the bromodurene is converted to 2,3,5,6-tetramethylbenzoic acid (melting at 175.5-179 C.) using 15.7 g. of ethyl bromide, 7.8 g. of magnesium and an excess of Dry Ice.

A mixture of 4 g. (0.0225 moles) of 2,3,5,6-tetramethylbenzoic acid, 4.3 g. (0.025 mole) of B-diethylaminoethyl chloride hydrochloride, 4.5 g. (0.045 mole) of potassium bicarbonate and 100 ml. of toluene is refluxed under a Stark and Dean trap for 22 hours. The reaction mixture, after cooling, is washed twice with 10% sodium hydroxide solution and once with water, and then dried over anhydrous magnesium sulfate. Anhydrous hydrogen chloride is then passed into the dry toluene solotion and the precipitate is collected. After recrystallization from a mixture of absolute alcohol and absolute ether, the resulting flediethylaminoethyl 2,3,5,6-tetrarnethylbenzoate hydrochloride melts at 192-194" C.

The calculated C and H analysis for C I-I O NCl is: C, 65.0; H, 9.0; that found is: C, 64.8; H, 9.1.

A 0.75% solution of this compound injected intracutaneously anesthetizes the skin of a guinea pig for 80-90 minutes. When applied to unbroken human skin as an ointment, the duration of anesthesia is about six times as long.

EXAMPLE 1V From g. of pentamethylbenzene and 26.7 g. of bromine, bromopentamethylbenzene, melting at 157-1595 C., is prepared following the procedure of Clement, Ann. Chim., 13, p. 243 (1940).

Following the procedure also set forth in the article cited in the foregoing paragraph, the bromopentamethylbenzene is converted to 2,3,4,5,6-pentamethylbenzoic acid (melting at 204-207 C.), using 29 g. of bromopentamethylbenzene, 14.3 g. of ethyl bromide, 7.3 g. of magnesium and excess Dry Ice.

A mixture of 8.3 g. (0.043 mole) of the 2,3,45,6- pentamethylbenzoic acid, 7.5 g. (0.044 mole) of B-diethylaminoethyl chloride hydrochloride, 9.6 g. (0.096 mole) of potassium bicarbonate and 175 ml. of toluene is refluxed under a Stark and Dean trap for 30 hours. The reaction mixture, after being allowed to cool, is washed twice with 10% sodium hydroxide solution and once with water, and then dried over anhydrous magnesium sulfate. The dried toluene solution is treated with anhydrous hydrogen chloride and the resulting precipitate is collected. After recrystallization from a mixture of absolute alcohol and absolute ether, the resulting fl-diethylaminoethyl 6 2,3,4, 5,6 pentamethylbenzoate hydrochloride melts at 204.5-2065" C.

The calculated C and analysis for C H O NCl is: C, 65.8; H, 9.2; that found is: C, 66.0; H, 9.4.

A 1% solution of this compound injected intracutaneously anesthetizes the skin of a guinea pig for -90 minutes.

In place of the ,B-diethylaminoethyl chloride hydrochoride in the foregoing procedure there may be employed 9 diethylaminopropyl chloride hydrochloride, [3 diethylaminoisopropyl chloride hydrochloride, p-diethylarninobutyl chloride hydrochloride, B-diethylaminosecondarybutyl chloride hydrochloride or [i-diethylaminoisobutyl chloride hydrochloride to prepare the corresponding fldiethylaminopropyl 2,3,4,5,6 pentamethylbenzoate hydrochloride, ,8 diethylaminoisopropyl 2,3,4,5,6 pentamethylbenzoate hydrochloride, ,8 diethylaminobutyl 2,3,4,5,6 pentamethylbenzoate hydrochloride, {3 diethylaminosecondarybutyl 2,3,4,S,6 pentamethylbenzoate hydrochloride and ,B-diethylaminoisobutyl 2,3,4,5,6-pentamethylbenzoate hydrochloride.

EXAMPLE V Following the procedure of Fuson and Corse, J. Am. Chem. Soc., 60, p. 2065 (1938), there is prepared 2,4,6- triethylbromobenzene, boiling at 92-94" C./ 4 mm., from 324 g. of 1,3,5-triethylbenzene, 10 g. of powdered iron and 320 g. of bromine.

Following the procedure also set forth in the article cited in the foregoing paragraph, 2,4,6-triethylbromobenzene (120.5 g.) is converted to 2,4,6-triethylbenzoic acid (melting at 113-114 C.), using 12.5 g. of magnesium and an excess of Dry Ice.

A mixture of 20.6 g. (0.1 mole) of 2,4,6-triethylbenzoic acid, 20 g. (0.2 mole) of potassium bicarbonate and 250 m1. of toluene is refluxed under a Stark and Dean trap for 17 hours. Then 17.2 g. (0.1 mole) of ,B-diethylaminoethyl chloride hydrochride are added, and the mixture is heated for an additional 111 hours. The reaction mixture is cooled and shaken once with a -1111. portion and twice with 50-ml. portions of 10% sodium hydroxide solution. The toluene layer is separated, Washed once with water and dried over anhydrous magnesium sulfate. Anhydrous hydrogen chloride is then bubbled through the toluene solution and the precipitate gathered and recrystallized from a mixture of absolute alcohol and absolute ether. The resulting fl-diethylaminoethyl 2,4,6-triethylbenzoate hydrochloride melts at 145.5-146.5 C.

The calculated C and H analysis for C H O NCl is: C, 66.7; H, 9.4; that found is: C, 66.4; H, 9.6.

A 1% solution of this compound injected intracutaneously anesthetizes the skin of a guinea pig for 45-60 minutes.

To prepare the corresponding fl-(butylethylamino) ethyl 2,4,6-triethylbenzoate hydrochloride, B-(butylethylamino) ethyl chloride hydrochloride may be employed in the foregoing procedure in place of the fi-diethylaminoethyl chloride hydrochloride.

EXAMPLE VI Following essentially the method of Fuson and Corse, J. Am. Chem. Soc., 60, p. 2065 (1938), 2,3,5,6-tetraethylbrornobenzene is prepared from 79 g. of tetraethylbenzene, 66 g. of bromine and 10 g. of iron powder. The product boils at 97-99" C./0.51 mm.

Following a modification of the procedure also set forth in the above-cited article, 72 g. of the 2,3,5,6-tetraethylbromobenzene is converted to 2,3,5,6-tetraethylbenzoic acid (melting at 106-1075 C.) using 54.5 g. of ethyl bromide, 18.9 g. of magnesium and excess Dry Ice. The modification consists of entraining the 2,3,5,6-tetraethylbromobenzene with ethyl bromide.

A mixture of 35.1 g. (0.15 mole) of the 2,3,5,6-tetraethylbenzoic acid, 30 g. (0.30 mole) of potassium bicarbonate and 250 ml. of toluene is heated under a Stark and Dean trap for about 20 hours. Then 25.8 g. (0.15 mole) of p-diethylaminoethyl chloride hydrochloride and 15 g. (0.15 mole) of potassium bicarbonate are added and heating is continued for an additional 114 hours. The reaction mixture is cooled and washed twice with 10% sodium bicarbonate solution and water. The toluene solution is dried over anhydrous magnesium sulfate and treated with dry hydrogen chloride. After crystallization from a mixture of absolute alcohol and absolute ether, the resulting B-diethylaminoethyl 2,3,5,6-tetraethylbenzoate hydrochloride melts at 151-152 C.

The calculated C and H analysis for C H NCl is: C, 68.2; H, 9.8; that found is: C, 67.8; H, 9.9.

Following the foregoing procedure, but employing fipiperidinoethyl chloride hydrochloride in place of the fl-diethylaminoethyl chloride hydrochloride, the corresponding e-piperidinoethyl 2,3,5,6-tetraethylbenzoate hydrochloride may be prepared.

EXAMPLE VII Following the procedure of Fuson and Horning, J. Am. Chem. Soc., 62, p. 2962 (1940), there is prepared from 408 g. of 1,3,5-triisopropylbenzene, 320 g. of bromine and 10 g. of iron powder, 478 g. of 2,4,6-triisopropylbromobenzene boiling at 145148 C./18 mm.

Following the procedure also set forth in the abovecited article, with the exception that the 2,4,6-triisopropylbromobenzene is entrained with ethyl bromide, 141.5 g. of the former compound are converted to 2,4,6- triisopropylbenzoic acid (melting at 182184 C.) using 5 ml. of ethyl bromide, 12.5 g. of magnesium and excess Dry Ice.

A mixture of 10.4 g. (0.04 mole) of the 2,4,6-triisopropylbenzoic acid, 8.3 g. (0.08 mole) of potassium bicarbonate and 250 ml. of toluene is refluxed for 8 hours under a Stark and Dean trap. Then 6.84 g. (0.04 mole) of fi-diethylaminoethyl chloride hydrochloride are added and refluxing is continued for an additional 22 hours. The reaction mixture is shaken twice with 10% sodium hydroxide solution and once with water. The toluene solution is dried over anhydrous magnesium sulfate and treated with dry hydrogen chloride. Following recrystallization of the resulting precipitate from a mixture of absolute alcohol and absolute ether, the fl-diethylaminoethyl 2,4,6-t1iisopropylbenzoate hydrochloride melts at 195.5197 C.

The calculated C and H analysis for C H O NCl is: C, 68.8; H, 10.0; that found is: C, 69.0; H, 10.2.

EXAMPLE VIII The p-diethylaminoethyl 2,3,5,6-tetramethyl benzoate of Example III is dissolved in isopropyl alcohol and the solution treated with an equimolar amount of fumaric acid. The solid which precipitates upon the addition of other is recrystallized from ethyl acetate to give fl-diethylaminoethyl 2,3,5,6-tetramethyl benzoate fumarate melting at 110-120 C.

The calculated nitrogen analysis for C H NO is: N, 3.6; that found is: N, 3.6.

The half lives, under hydrolysis conditions, of certain of the compounds of the foregoing examples were determined and compared with those of related compounds. The procedure employed is the modification of that of Tommila et al; as described by Price and Lincoln, J. Am. Chem. Soc., 73, p. 5836 (1951). This procedure measures the length of time required to hydrolyze half of the material tested under standard conditions.

Considerable modification is possible in the selection of the various substituents and salt forms without departing from the scope of the present invention.

I claim:

1. ,B-Substituted aminoalkyl 2,6-substituted benzoate compounds having the fundamental structure:

R1 (i1 0 RaN R1 R: R.

R RI

where R and R are alkyl groups containing from 1 to 3 carbon atoms; where R R and R are selected from the group consisting of hydrogen and alkyl groups containing from 1 to 3 carbon atoms; where R is a saturated aliphatic chain containing from 2 to 4 carbon atoms, and where R; and R are selected from the group consisting of alkyl groups containing from 1 to 4 carbon atoms, the

total number of carbon atoms in R plus R not exceeding 6, and a pentamethylene linkage,

O s-C 2 cH,

orig-0Q,

2. fl-Diethylaminoethyl 2,6-dialky1 substituted benzoate compounds having the fundamental structure:

CHQCHI (J-0 CHiCHi CHzCH R1 R1 where R and R are alkyl groups containing froml to 3 carbon atoms, and where R R and R are selected from the group consisting of hydrogen and alkyl group containing from 1 to 3 carbon atoms.

3. p-Diethylaminoethyl 2,6-dimethyl benzoate compounds having the fundamental structure:

CHgCH (ll-O GHaCHsN' CHgOH CH CH;

4. B-Diethylaminoethyl 2,6-dimethyl benzoate hydrochloride,

10 5. fl-Diethylaminoethyl 2,4,6-trimethyl benzoate com- 10. B-Diethylarninoethyl 2,3,4,5,6-pentamethyl benzopounds having the fundamental structure: ate hydrochloride.

011 011, 11. fl-Diethylaminoethyl 2,4,6-triethyl benzoate com- CZOCHBCHZN 5 pounds having the fundamental structure:

CHzCH: 0 CH2CH3 CH3 CH3 C-OCHaCHzN I OHzCH; CHaCH CHQOH:

H3 6. fi-Diethylaminoethyl 2,4,6-trimethyl benzoate hydrochloride. CHzCH:

fiy f y 2,3,5,64etramethyl bellzoate 12. B-Diethylaminoethyl 2,4,6-triethyl benzoate hydrocompounds havmg the fundamental structure: 1 -i OHzOH; Z CHZCHN References Cited in the file of this patent UNITED STATES PATENTS OH 817,164 Ernilewicz Apr. 10, 1906 1,193,651 Wildman et al. Aug. 8, 1916 CH5 CH3 FOREIGN PATENTS fi-Diethylaminoethyl 2,3,5,6-tet1'amethyl benzoate 49 4 Great Britain June 4 1931 hydrochloride.

9. fl-Diethylaminoethyl 2,3,4,5,6-pentamethyl benzoate OTHER REFERENCES compounds having the fundamental structure: Dovoretzky et 211.: J. Org. Chem, 18, 615 to 619 (1953).

O CHBOH! (|3OCH2CH2N H H CH3- CH3 0 2C s CH: CH: 

1. B-SUBSTITUTED AMINOALKYL 2,6-SUBSTITUTED BENZOATE COMPOUND HAVING THE FUNDAMENTAL STRUCTURE: 